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Syringic Acid Extracted from Herba dendrobii Prevents Diabetic Cataract Pathogenesis by Inhibiting Aldose Reductase Activity.

ABSTRACT: Objective. Effects of Syringic acid (SA) extracted from dendrobii on diabetic cataract (DC) pathogenesis were explored. Methods. Both in vitro and in vivo DC lens models were established using D-gal, and proliferation of HLEC exposed to SA was determined by MMT assay. After 60-day treatment with SA, rat lens transparency was observed by anatomical microscopy using a slit lamp. SA protein targets were extracted and isolated using 2-DE and MALDI TOF/TOF. AR gene expression was investigated using qRT-PCR. Interaction sites and binding characteristics were determined by molecule-docking techniques and dynamic models. Results. Targeting AR, SA provided protection from D-gal-induced damage by consistently maintaining lens transparency and delaying lens turbidity development. Inhibition of AR gene expression by SA was confirmed by qRT-PCR. IC(50) of SA for inhibition of AR activity was 213.17??g/mL. AR-SA binding sites were Trp111, His110, Tyr48, Trp20, Trp79, Leu300, and Phe122. The main binding modes involved hydrophobic interactions and hydrogen bonding. The stoichiometric ratio of non-covalent bonding between SA and AR was 1.0 to 13.3. Conclusion. SA acts to prevent DC in rat lenses by inhibiting AR activity and gene expression, which has potential to be developed into a novel drug for therapeutic management of DC.

SUBMITTER: Wei X

PROVIDER: S-EPMC3545393 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Syringic Acid Extracted from Herba dendrobii Prevents Diabetic Cataract Pathogenesis by Inhibiting Aldose Reductase Activity.

Wei Xiaoyong X Chen Dan D Yi Yanchun Y Qi Hui H Gao Xinxin X Fang Hua H Gu Qiong Q Wang Ling L Gu Lianquan L

Evidence-based complementary and alternative medicine : eCAM 20121229

Objective. Effects of Syringic acid (SA) extracted from dendrobii on diabetic cataract (DC) pathogenesis were explored. Methods. Both in vitro and in vivo DC lens models were established using D-gal, and proliferation of HLEC exposed to SA was determined by MMT assay. After 60-day treatment with SA, rat lens transparency was observed by anatomical microscopy using a slit lamp. SA protein targets were extracted and isolated using 2-DE and MALDI TOF/TOF. AR gene expression was investigated using q ...[more]

PMID: 23365598

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Project description:Long-term metabolic aberrations contribute to the development of diabetic neuropathy but the precise mechanism or mechanisms remains elusive. We have previously shown that aldose reductase-deficient mice exhibit delayed onset and progression of neuropathy following induction of diabetes, suggesting a role both for downstream metabolites of this enzyme and also for other unrelated pathways. In this study, we have utilized comprehensive metabolomics analyses to identify potential neurotoxic metabolites in nerve of diabetic mice and explored the mechanism of peripheral nerve injury. Aldose reductase knockout and control C57Bl/6J mice were made diabetic by injection of streptozotocin and followed for 8-16 weeks. Diabetic aldose reductase knockout mice exhibited delayed onset of nerve conduction slowing compared to diabetic wild-type mice. The sciatic nerves from aldose reductase knockout mice exposed to 12 weeks of diabetes were used for metabolomics analysis and compared with analyses of nerves from age-matched diabetic wild-type mice as well as non-diabetic aldose reductase knockout and wild-type mice. Neurotoxicity of candidate metabolites was evaluated using cultured Schwann cells and dorsal root ganglion neurons, and further confirmed in vivo. Metabolomics analysis identified elevated glucosamine levels in both diabetic aldose reductase knockout and diabetic wild mice. Exposure to glucosamine reduced survival of cultured Schwann cells and neurons accompanied by increased expression of cleaved caspase 3, CCAT-enhancer-binding homologous protein and mitochondrial hexokinase-I, along with ATP depletion. These changes were suppressed by siRNA to hexokinase-I or the ATP donor, inosine, but not by the antioxidant N-acetylcysteine or the endoplasmic reticulum-stress inhibitor 4-phenylbutyrate. The O-GlcNAcylation enhancer, O-(2-acetamido-2-deoxy-d-glucopyranosylidene) amino N-phenylcarbamate, did not augment glucosamine neurotoxicity. Single dose glucosamine injection into mice caused a reduction of sciatic nerve Na, K-ATPase activity, ATP content and augmented expression of hexokinase-I, which were suppressed by pretreatment with inosine but not with 4-phenylbutyrate. Mice implanted with a subcutaneous pump to infuse glucosamine for 12 weeks developed nerve conduction slowing and intraepidermal nerve fibre loss, recapitulating prominent indices of diabetic neuropathy. While acute glucosamine neurotoxicity is unlikely to contribute substantially to the slowly developing neuropathy phenotype in humans, sustained energy deprivation induced by glucosamine may well contribute to the pathogenesis of diabetic neuropathy. Our data thus identifies a novel pathway for diabetic neuropathy that may offer a potential new therapeutic target.

Dataset Information

Syringic Acid Extracted from Herba dendrobii Prevents Diabetic Cataract Pathogenesis by Inhibiting Aldose Reductase Activity.

Publications

Syringic Acid Extracted from Herba dendrobii Prevents Diabetic Cataract Pathogenesis by Inhibiting Aldose Reductase Activity.

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